The molecular and phenotypic spectrum of IQSEC2-related epilepsy

Ayelet Zerem, Kazuhiro Haginoya, Dorit Lev, Lubov Blumkin, Sara Kivity, Ilan Linder, Cheryl Shoubridge, Elizabeth Emma Palmer, Michael Field, Jackie Boyle, David Chitayat, William D. Gaillard, Eric H Kossoff, Marjolaine Willems, David Geneviève, Frederic Tran-Mau-Them, Orna Epstein, Eli Heyman, Sarah Dugan, Alice Masurel-Paulet & 9 others Ame'lie Piton, Tjitske Kleefstra, Rolph Pfundt, Ryo Sato, Andreas Tzschach, Naomichi Matsumoto, Hirotomo Saitsu, Esther Leshinsky-Silver, Tally Lerman-Sagie

Research output: Contribution to journalArticle

Abstract

Objective: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. Methods: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. Results: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. Significance: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

Original languageEnglish (US)
JournalEpilepsia
DOIs
StateAccepted/In press - 2016

Fingerprint

Epilepsy
Brain Diseases
Seizures
Intellectual Disability
Absence Epilepsy
Spasm
X-Linked Genes
Muscle Hypotonia
Strabismus
Age of Onset
Communication
Magnetic Resonance Imaging
Brain

Keywords

  • Epileptic encephalopathy
  • Exome sequencing
  • Intellectual disability
  • X-linked

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Zerem, A., Haginoya, K., Lev, D., Blumkin, L., Kivity, S., Linder, I., ... Lerman-Sagie, T. (Accepted/In press). The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia. https://doi.org/10.1111/epi.13560

The molecular and phenotypic spectrum of IQSEC2-related epilepsy. / Zerem, Ayelet; Haginoya, Kazuhiro; Lev, Dorit; Blumkin, Lubov; Kivity, Sara; Linder, Ilan; Shoubridge, Cheryl; Palmer, Elizabeth Emma; Field, Michael; Boyle, Jackie; Chitayat, David; Gaillard, William D.; Kossoff, Eric H; Willems, Marjolaine; Geneviève, David; Tran-Mau-Them, Frederic; Epstein, Orna; Heyman, Eli; Dugan, Sarah; Masurel-Paulet, Alice; Piton, Ame'lie; Kleefstra, Tjitske; Pfundt, Rolph; Sato, Ryo; Tzschach, Andreas; Matsumoto, Naomichi; Saitsu, Hirotomo; Leshinsky-Silver, Esther; Lerman-Sagie, Tally.

In: Epilepsia, 2016.

Research output: Contribution to journalArticle

Zerem, A, Haginoya, K, Lev, D, Blumkin, L, Kivity, S, Linder, I, Shoubridge, C, Palmer, EE, Field, M, Boyle, J, Chitayat, D, Gaillard, WD, Kossoff, EH, Willems, M, Geneviève, D, Tran-Mau-Them, F, Epstein, O, Heyman, E, Dugan, S, Masurel-Paulet, A, Piton, A, Kleefstra, T, Pfundt, R, Sato, R, Tzschach, A, Matsumoto, N, Saitsu, H, Leshinsky-Silver, E & Lerman-Sagie, T 2016, 'The molecular and phenotypic spectrum of IQSEC2-related epilepsy', Epilepsia. https://doi.org/10.1111/epi.13560
Zerem A, Haginoya K, Lev D, Blumkin L, Kivity S, Linder I et al. The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia. 2016. https://doi.org/10.1111/epi.13560
Zerem, Ayelet ; Haginoya, Kazuhiro ; Lev, Dorit ; Blumkin, Lubov ; Kivity, Sara ; Linder, Ilan ; Shoubridge, Cheryl ; Palmer, Elizabeth Emma ; Field, Michael ; Boyle, Jackie ; Chitayat, David ; Gaillard, William D. ; Kossoff, Eric H ; Willems, Marjolaine ; Geneviève, David ; Tran-Mau-Them, Frederic ; Epstein, Orna ; Heyman, Eli ; Dugan, Sarah ; Masurel-Paulet, Alice ; Piton, Ame'lie ; Kleefstra, Tjitske ; Pfundt, Rolph ; Sato, Ryo ; Tzschach, Andreas ; Matsumoto, Naomichi ; Saitsu, Hirotomo ; Leshinsky-Silver, Esther ; Lerman-Sagie, Tally. / The molecular and phenotypic spectrum of IQSEC2-related epilepsy. In: Epilepsia. 2016.
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title = "The molecular and phenotypic spectrum of IQSEC2-related epilepsy",
abstract = "Objective: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. Methods: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. Results: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50{\%}) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. Significance: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.",
keywords = "Epileptic encephalopathy, Exome sequencing, Intellectual disability, X-linked",
author = "Ayelet Zerem and Kazuhiro Haginoya and Dorit Lev and Lubov Blumkin and Sara Kivity and Ilan Linder and Cheryl Shoubridge and Palmer, {Elizabeth Emma} and Michael Field and Jackie Boyle and David Chitayat and Gaillard, {William D.} and Kossoff, {Eric H} and Marjolaine Willems and David Genevi{\`e}ve and Frederic Tran-Mau-Them and Orna Epstein and Eli Heyman and Sarah Dugan and Alice Masurel-Paulet and Ame'lie Piton and Tjitske Kleefstra and Rolph Pfundt and Ryo Sato and Andreas Tzschach and Naomichi Matsumoto and Hirotomo Saitsu and Esther Leshinsky-Silver and Tally Lerman-Sagie",
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T1 - The molecular and phenotypic spectrum of IQSEC2-related epilepsy

AU - Zerem, Ayelet

AU - Haginoya, Kazuhiro

AU - Lev, Dorit

AU - Blumkin, Lubov

AU - Kivity, Sara

AU - Linder, Ilan

AU - Shoubridge, Cheryl

AU - Palmer, Elizabeth Emma

AU - Field, Michael

AU - Boyle, Jackie

AU - Chitayat, David

AU - Gaillard, William D.

AU - Kossoff, Eric H

AU - Willems, Marjolaine

AU - Geneviève, David

AU - Tran-Mau-Them, Frederic

AU - Epstein, Orna

AU - Heyman, Eli

AU - Dugan, Sarah

AU - Masurel-Paulet, Alice

AU - Piton, Ame'lie

AU - Kleefstra, Tjitske

AU - Pfundt, Rolph

AU - Sato, Ryo

AU - Tzschach, Andreas

AU - Matsumoto, Naomichi

AU - Saitsu, Hirotomo

AU - Leshinsky-Silver, Esther

AU - Lerman-Sagie, Tally

PY - 2016

Y1 - 2016

N2 - Objective: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. Methods: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. Results: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. Significance: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

AB - Objective: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. Methods: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. Results: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. Significance: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

KW - Epileptic encephalopathy

KW - Exome sequencing

KW - Intellectual disability

KW - X-linked

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